Water → 4-(4-Chloro-2-fluoroanilino)-7-((2-cyano4-pyridyl)methoxy)-6-methoxyquinazoline

HRID 1384614Notes

Reaction equation

HRID 1384614 reaction equation
[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][C:26]4[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1

Participants

6

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 226250684-(Chloromethyl)picolinonitrile hydrochlorideHCID 1355137204-(4-Chloro-2-fluorophenylamino)-7-hydroxy-6-methoxyquinazoline

Product 1

HCID 226250774-(4-Chloro-2-fluoroanilino)-7-((2-cyano4-pyridyl)methoxy)-6-methoxyquinazolineYield 4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (600 mg, 2 mmol), (prepared as described for the starting material in Example 24), 4-chloromethyl-2-cyanopyridine hydrochloride (620 mg, 3 mmol) and potassium carbonate (1.0 g 7 mmol) in DMF (8 ml) was heated at 80° C. for 30 minutes. The mixture was allowed to cool, poured into water and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and the solvent removed by evaporation and azeotroped with toluene. The residue was triturated with ethyl acetate/hexane, the solid product collected by filtration and purified by column chromatography eluting with ethyl acetate and further chromatography eluting with methylene chloride/methanol (99/1). The purified product was recrystallised from ethyl acetate/hexane to give 4-(4-chloro-2-fluoroanilino)-7-((2-cyano-4-pyridyl)methoxy)-6-methoxyquinazoline (35 mg, 4%). m.p. 209-213° C. 1H NMR Spectrum: (DMSOd6) 3.98(s, 3H); 5.44(s, 2H); 7.26(s, 1H); 7.34(dd, 1H); 7.53(dd, 1H); 7.58(d, 1H); 7.80(d, 1H); 7.85(s, 1H); 8.27(s, 1H); 8.35(s, 1H); 8.80(d, 1H); 9.60(s, 1H) MS-ESI: 436 [MH]+

Workup

  1. custom(prepared
  2. temperatureto cool
  3. extractionextracted with ethyl acetate
  4. dry with materialThe combined extracts were dried (MgSO4)
  5. customthe solvent removed by evaporation
  6. customazeotroped with toluene
  7. customThe residue was triturated with ethyl acetate/hexane
  8. filtrationthe solid product collected by filtration
  9. custompurified by column chromatography
  10. washeluting with ethyl acetate and further chromatography
  11. washeluting with methylene chloride/methanol (99/1)
  12. customThe purified product was recrystallised from ethyl acetate/hexane

Sources & evidence

ORD record
ord-aa2784e9ba22434b80af9ddba848319f
Source dataset
uspto-grants-2001_07
Patent number
US06258951B1

Reaction notes

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